PROJECT SUMMARY/ABSTRACT (DEVELOPMENTAL THERAPEUTICS) Members of the Developmental Therapeutics (DT) Program use breakthrough insights made in the UMCCC basic science programs to drive the discovery of first-in-class small molecule anticancer agents that can be advanced into biomarker-driven clinical trials. The Program serves as the forum for investigators with shared interest in pre-clinical development of novel targets, agents, therapeutic combinations or natural product-based drugs that either perturb protein-protein interactions, inhibit kinase activity, target epigenetic modifiers or function as radiation sensitizers. The DT Program comprises 31 members from 18 departments and five schools across the University of Michigan. Total annual direct research support is $15.2M, with $4.1M (27%) from the NCI, $3M (19%) from other NIH support and $3.7M (24.2%) from other peer-reviewed sources. During the last funding period, and in close collaboration with the Structure and Drug Screening as well as Pharmacokinetics Shared Resources, DT Program members authored 547 publications, of which 22.1% are intra-programmatic and 35.8% are inter-programmatic. To further these advances, DT Program research is focused on one or more of the following Specific Aims: 1) validation of novel cancer targets that are amenable to pharmacological intervention, 2) discovery, optimization and evaluation of therapeutic agents and potential biomarkers of response in clinically relevant preclinical model systems, and 3) advancement of preclinical proof-of-concept studies into biomarker-enabled clinical trials through structured collaborations between DT Program members and TACR-based clinical investigator teams. By incorporating clinical investigators in the design of preclinical studies at the pre-IND stage, the DT Program seeks to streamline clinical drug development while improving the likelihood of clinical successes. 1